Summary Obesity is a leading cause of chronic illness and premature death in the U.S. A promising avenue to reduce obesity and associated diseases is through increasing the activity of energy-burning brown and beige adipocytes. In addition to promoting fat loss, brown fat cells have the capacity to consume large amounts of lipid and glucose and thereby reduce their toxic actions in many tissues. PRDM16, a zinc-finger transcription factor plays a critical role in regulating brown and beige adipocyte differentiation. We recently discovered that, in addition to driving a brown fat-selective gene program, PRDM16 powerfully suppresses transcriptional responses to innate immune type 1 Interferon (IFN) signaling in adipose cells and tissues. Moreover, we found that Type 1 IFN signaling, which is primarily associated with viral infection, is elevated in adipose tissues by high fat diet and that type 1 IFN activation represses mitochondrial function in adipocytes. These exciting findings led us to hypothesize that PRDM16-mediated suppression of Type 1 IFN-signaling preserves the thermogenic function of brown fat under normal physiological conditions. However, we speculate that persistent increases in type 1 IFN signaling caused by high fat diet leads to mitochondrial dysfunction in brown fat and, in doing so, contributes significantly to the development of systemic metabolic disease. In this project, we will investigate the mechanisms by which PRDM16 blocks the IFN-response in adipose cells and determine the role of type 1 IFN in driving high fat diet-induced weight gain and systemic insulin resistance. In aim 1, we will determine the mechanism by which PRDM16 is recruited to IFN-responsive genes and study how PRDM16 functions in chromatin to repress the transcription of these genes. In aim 2, we will use cell culture and in vivo genetic models to examine the interaction between PRDM16 and type 1 IFN-signaling in regulating brown fat function. In Aim 3, we will determine if blocking high fat diet-linked type 1 IFN-responses in adipose could be used to reduce metabolic disease. Altogether, these studies will define a novel role for PRDM16 and type 1 IFN signaling in regulating adipose biology and systemic metabolism.